1. Field of the Invention
The present invention relates to a method for treatment in gene therapy and use of the specified guanine derivative as the pharmaceutical agent for gene therapy of tumor, restenosis after PTCA and graft vs. host diseases; more specifically, the present invention relates to a method for treatment in gene therapy, comprising the step of administering (administrating) as the pharmaceutical agent for gene therapy, (-)-9-[1'S,2'R-bis(hydroxymethyl)cyclopropan-1'-yl]methylguanine or a derivative convertible to the guanine derivative in animal bodies, into a living subject such as humans; still more specifically, the present invention relates to an use of the guanine derivative as the pharmaceutical agent for gene therapy, wherein the guanine derivative as the pharmaceutical agent is used in combination with the gene used for the gene therapy, which is preferably the gene of an enzyme phosphorylating the guanine derivative, more preferably thymidine kinase gene, particularly the thymidine kinase gene of a virus (for example, herpesvirus).
2. Description of the Related Art
Clinical modalities of the gene therapy of cancer include the following:
1. a modality directly targeting cancer-related genes, comprising introducing cancer suppresser genes such as P53 gene and antisense genes of cancer genes into cancer cells; PA0 2. a modality enhancing immunity against cancer, comprising introducing various cytokine genes and syngenic MHC genes into tumor-infiltrating lymphocytes and cancer cells; PA0 3. a modality introducing suicide genes into cancer cells to permit the cancer cells to be sensitive to drugs, comprising introducing the herpesvirus-thymidine kinase gene (HSV-TK gene) into cancer cells and administering ganciclovir (GCV) as a therapeutic agent of herpesvirus, to kill the cancer cells; and PA0 4. a modality comprising introducing a multi-resistant gene into hematopoietic cells to enhance the resistance against anti-cancer agents and subsequently subjecting the cancer cells to chemical therapies at large doses (see MATSUSHITA Eiki et al., Liver, Gall Bladder and Spleen 34(4): 433-438, 1997). PA0 1. The method described above wherein the gene therapy is for the therapeutic treatment with suicide gene therapy. PA0 2. The method described above wherein the treatment is for the therapeutic treatment of humans afflicted with any of tumor, restenosis and graft vs. host diseases. PA0 3. The method as describe above wherein the pharmaceutical agent of the guanine derivative is for parenteral dosing, particularly intravenous dosing at 0.001 to 10,000 mg/kg per day to humans or for oral dosing at 0.005 to 50,000 mg/kg per day to humans which may be administered thereinto. PA0 4. The method described above wherein the pharmaceutical agent (the guanine derivative) for gene therapy is used in combination with the gene of an enzyme phosphorylating the guanine derivative described above, preferably thymidine kinase gene, more preferably viral thymidine kinase gene. PA0 5. The method described above wherein the gene of an enzyme phosphorylating the guanine derivative is the thymidine kinase gene of herpesvirus (including HSV-1, HSV-2 and VZV). PA0 6. The method described above wherein the thymidine kinase gene is a gene carried on a viral vector to be inserted in a target cell. PA0 7. The method described above wherein the guanine derivative for the effective component in the pharmaceutical agent is the compound represented by the structural formula (1), and at least one hydroxyl group of the hydroxymethyl group thereof is esterified with amino acid.
Clinical protocols using such modalities have been approved for various subjects of cancers, such as melanoma, cerebral tumor, breast cancer, large intestine cancer including colon cancer, lung cancer, ovarian cancer, and kidney cancer. A clinical protocol using the modality described above in 3 has been reported for hepatocellular carcinoma (see Huber, BE, Richards CA, Krenisky TA: Retroviral mediated gene therapy for the treatment of hepatocellular carcinoma: An innovative approach for cancer therapy. Proc. Natl. Acad. Sci. USA 88: 8039-8043, 1991). Recently, a clinical report about cerebral tumor has been issued (see Ram Z. et al., Nat. Med. 3(12), p.1354-1361, 1997).